aids an non aids morbidity and mortality 2012

H I V / A I D S M A J O R A R T I C L E

AIDS and Non-AIDS Morbidity and MortalityAcross the Spectrum of CD4 Cell Counts inHIV-Infected Adults Before StartingAntiretroviral Therapy in Cote d’Ivoire

Xavier Anglaret,1,3 Albert Minga,1,3 Delphine Gabillard,1,3 Timothee Ouassa,3,4 Eugene Messou,1,3 Brandon Morris,6

Moussa Traore,3 Ali Coulibaly,3 Kenneth A. Freedberg,5,6,7 Charlotte Lewden,1,3 Herve Menan,3,4 Yao Abo,3

Nicole Dakoury-Dogbo,3 Siaka Toure,3 Catherine Seyler,2,3 and The ANRS 12222 Morbidity/Mortality Study Groupa

1INSERM U897 and the Universite Bordeaux Segalen, Bordeaux, 2Service de Sante Publique et d'Information Medicale, Hopital de la Timone, Marseille,France; 3Programme PAC-CI, CHU de Treichville, 4Centre de Diagnostic et de Recherche sur le SIDA (CeDReS), CHU de Treichville, Abidjan, Cote d'Ivoire;5Divisions of Infectious Disease and General Medicine and Medical Practice Evaluation Center, 6Department of Medicine, Massachusetts GeneralHospital, Harvard University Center for AIDS Research, Harvard Medical School, and 7Department of Health Policy and Management, Harvard Schoolof Public Health, Boston, Massachusetts

Background. In Western Europe, North America, and Australia, large cohort collaborations have been able to estimate

the short-term CD4 cell count–specific risk of AIDS or death in untreated human immunodeficiency virus (HIV)–

infected adults with high CD4 cell counts. In sub–Saharan Africa, these CD4 cell count–specific estimates are scarce.

Methods. From 1996 through 2006, we followed up 2 research cohorts of HIV-infected adults in Cote d’Ivoire.

This included follow-up off antiretroviral therapy (ART) across the entire spectrum of CD4 cell counts before the

ART era, and only in patients with CD4 cell counts .200 cells/lL once ART became available. Data were censored

at ART initiation. We modeled the CD4 cell count decrease using an adjusted linear mixed model. CD4 cell count–

specific rates of events were obtained by dividing the number of first events occurring in a given CD4 cell count

stratum by the time spent in that stratum.

Results. Eight hundred sixty patients were followed off ART over 2789 person-years (PY). In the $650, 500–649,

350–499, 200–349, 100–199, 50–99, and 0–49 cells/lL CD4 cell count strata, the rates of AIDS or death were 0.9, 1.7,

3.7, 10.4, 30.9, 60.8, and 99.9 events per 100 PY, respectively. In patients with CD4 cell counts $200 CD4 cells/lL,

the most frequent AIDS-defining disease was tuberculosis (decreasing from 4.0 to 0.6 events per 100 PY for 200–349

and$650 cells/lL, respectively), and the most frequent HIV non-AIDS severe diseases were visceral bacterial diseases

(decreasing from 9.1 to 3.6 events per 100 PY).

Conclusions. Rates of AIDS or death, tuberculosis, and invasive bacterial diseases are substantial in patients

with CD4 cell counts $200 cells/lL. Tuberculosis and bacterial diseases should be the most important outcomes in

future trials of early ART in sub–Saharan Africa.

CD4 lymphocyte count is one of the most important

determinants of human immunodeficiency virus (HIV)–

related morbidity and mortality. In Western Europe,

North America, and Australia, large cohort collabo-

rations have been able to estimate the short-term CD4

cell count–specific risk of AIDS or death in untreated

HIV-infected adults across a wide spectrum of CD4 cell

counts [1, 2]. On the basis of these estimates, recent

models suggested that CD4 cell counts of 350 cells/lL

was the minimum threshold to start antiretroviral

treatment (ART) but that there might be benefits to

starting earlier [3, 4]. Several trials of early ART are

ongoing to address the latter issue.

In sub–Saharan Africa, knowledge about HIV-related

morbidity and mortality in untreated patients comes from

Received 12 July 2011; accepted 28 October 2011; electronically published 14December 2011.

aThe ANRS 12222 Morbidity/Mortality Study Group members are listed in theAcknowledgments section.Correspondence: Xavier Anglaret, MD, PhD, Programme PAC-CI, CHU de

Treichville, 18 BP 1954, Abidjan, Cote d'Ivoire ([email protected]).

Clinical Infectious Diseases 2012;54(5):714–23� The Author 2011. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]: 10.1093/cid/cir898

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a limited number of studies. Most were cross-sectional hospital-

based studies [5, 6]; very few were longitudinal [7, 8]. Of the

latter, some were performed in the 1990s, when CD4 cell counts

were not available, and most of the others described morbidity

based on baseline and not follow-up CD4 cell counts [9–11]. Data

are especially lacking in patients with high CD4 cell counts.

Because of the incompleteness of existing data, it remains un-

clear whether HIV infection treatment guidelines should be re-

gion-specific. There is extensive evidence showing that some

infectious diseases, such as tuberculosis, are more frequent in sub–

Saharan Africa than in Europe or in the United States, both in the

general population and in the HIV-infected population [12–17].

However, because CD4 cell count–specific rates of these diseases

have not been estimated across the entire spectrum of CD4 cell

counts before the ART era, the question of whether patients with

similar CD4 cell counts should have different guidelines, de-

pending on the region in which they live, has not been clearly

addressed. This is particularly true when it comes to the crucial

question of when to start ART.

In this study, we describe the CD4 cell count–specific rates of

morbidity and mortality across the full spectrum of CD4 cell

counts in 2 cohorts of untreated HIV-infected adults. These

cohort studies were funded by the French Agence Nationale de

Recherche sur le SIDA (ANRS) in Cote d’Ivoire.

METHODS

Patients and Follow-upWe collected data from 2 large cohort studies in Cote d’Ivoire.

Both cohorts started at the end of the 1990s, before ART was

available in Africa, and were followed up by the same team and

with similar procedures. In both cohorts, CD4 cell counts were

measured every 6 months in all patients, and documentation of

morbidity was the primary goal.

The cohorts have been described elsewhere. In summary, the

ANRS 1203 study was followed up in Abidjan from 1996

through 2003. It was a prevalent cohort of adults who were

already HIV-infected when they were enrolled and for whom the

date of seroconversion was unknown [18]. The ANRS 1220

study is a cohort of adult HIV-infected blood donors whose date

of seroconversion was estimated. Follow-up started in 1997 at

the National Blood Bank of Abidjan and is ongoing [19].

The 2 cohorts were followed up similarly, and had in com-

mon (1) the objective of documenting morbidity, (2) CD4 cell

count tests every 6 months, (3) the conditions of access to care,

with all tests and treatment free of charge, (4) the types of re-

corded morbidities and standardized definitions, and (5) tracing

procedures for patients lost to follow-up.

Recorded MorbiditiesIn both cohorts, the following events were systematically recorded:

all World Health Organization (WHO) stages 2, 3, or 4 diseases or

Centers for Disease Control and Prevention (CDC) stage 3 de-

fining diseases; malaria; bacterial and fungal mucocutaneous in-

fections; bacterial and parasitic enteritis; and all other morbidity

events that had at least 1 of the following criteria: fever of .38�C,

at least 1 day in the hospital (including day-care hospital), or

leading to death. Furthermore, when a disease was classified at

a WHO or CDC stage on the basis of a recurrent episode

(eg, upper respiratory tract infection) or of an episode lasting

.1 month (eg, unexplained fever or unexplained diarrhea), first

episodes and episodes lasting ,1 month were also recorded. Each

episode of morbidity was reviewed by an event documentation

committee (standardized criteria are shown in Supplementary

Appendix 1 for the most frequent diseases).

Table 1. Characteristics of Participants and Follow-up of ANRS1203 and 1220 Cohorts, Abidjan, Cote d'Ivoire

Characteristic

No. (%) of

Participants

(N 5 860)

Primo-CI ANRS 1220 cohort 246

Cotrame ANRS 1203 cohort 614

Female sex 522 (61)

Age, years, median (IQR) 30 (25–36)

Baseline CD4 cell count,cells/lL, mean (SD)

392 (265)

Baseline WHO stage

1 266 (31)

2 227 (26)

3 294 (34)

4 71 (8)

Overall follow-up,months, median (IQR)

35.9 (18.0–59.0)

No. of CD4 cell countsper patient, median (IQR)

6 (3–9)

Follow-up in CD4 cellcount stratum, person-years

.650 cells/lL 358

501–650 cells/lL 359

351–500 cells/lL 612

201–350 cells/lL 759

101–200 cells/lL 408

51–100 cells/lL 151

0–50 cells/lL 141

Status at study termination

Alive without ART 293 (34)

Lost to follow-up before ART initiation 73 (8)

Censored at ART initiation 232 (24)

Dead before ART initiation 262 (33)

Data are no. (%) of participants, unless otherwise indicated.

Abbreviations: ANRS, French Agence Nationale de Recherche sur le SIDA;

ART, antiretroviral therapy; IQR, interquartile range; SD, standard deviation;

WHO, World Health Organization.

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Table 2. WHO Stages 2–4 Diseases and Diseases With Hospital Admission or Bacteremia in ANRS 1203 and 1220 Cohorts, Abidjan,Cote d'Ivoire

Disease

No. of

Episodes

Overall

No. (%) of

Episodes

With Hospital

Admission

No. (%) of

Episodes With

Bacteremia

Classification, No. (%) of Episodes

WHO

Stage 2

WHO

Stage 3

WHO

Stage 4 AIDS

Mycobacterial diseases

Tuberculosis 84 54 (6) 4 (3) 0 (0) 55 (5) 29 (10) 84 (24)

Nontuberculousmycobacteriosis

31 28 (3) 31 (23) 0 (0) 0 (0) 31 (10) 31 (9)

Bacterial diseases

Pneumonia 50 38 (4) 14 (10) 0 (0) 41 (4) 9 (3) 9 (3)

Isolated bacteremia 59 41 (4) 59 (43) 0 (0) 49 (5) 10 (3) 10 (3)

Pyelonephritis 24 20 (2) 2 (1) 0 (0) 24 (2) 0 (0) 0 (0)

Prostatitis 10 6 (1) 1 (1) 0 (0) 10 (1) 0 (0) 0 (0)

Orchitis/ epididymitis 7 3 (,1) 0 (0) 0 (0) 7 (1) 0 (0) 0 (0)

Salpingitis 4 3 (,1) 0 (0) 0 (0) 4 (,1) 0 (0) 0 (0)

Bacterial enteritis 90 46 (5) 17 (12) 0 (0) 88 (9) 2 (1) 2 (1)

Other bacterial invasivediseasea

10 8 (1) 4 (3) 0 (0) 10 (1) 0 (0) 0 (0)

Otitis 104 11 (1) 0 (0) 35 (5) 0 (0) 0 (0) 0 (0)

Sinusitis 119 26 (3) 4 (3) 43 (6) 4 (1) 0 (0) 0 (0)

Mucocutaneous infections 242 8 (1) 1 (1) 0 (0) 2 (,1) 0 (0) 0 (0)

Fungal diseases

Oral candidiasis 676 1 (,1) 0 (0) 0 (0) 676 (66) 0 (0) 0 (0)

Vaginal candidiasis 390 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Esophageal candidiasis 110 7 (1) 0 (0) 0 (0) 0 (0) 110 (37) 110 (31)

Cryptococcosis 15 15 (2) 0 (0) 0 (0) 0 (0) 15 (5) 15 (4)

Histoplasmosis 1 1 (,1) 0 (0) 0 (0) 0 (0) 1 (,1) 1 (,1)

Angular cheilitis 135 1 (,1) 0 (0) 135 (20) 0 (0) 0 (0) 0 (0)

Fungal nail infections 68 0 (0) 0 (0) 68 (10) 0 (0) 0 (0) 0 (0)

Other fungal skininfections

454 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Virologic diseases

Herpes zoster virusinfection

149 12 (1) 0 (0) 149 (22) 0 (0) 0 (0) 0 (0)

Genital HSV infection 173 0 (0) 0 (0) 0 (0) 0 (0) 18 (6) 18 (5)

Visceral HSV or CMVinfection

8 4 (,1) 0 (0) 0 (0) 0 (0) 8 (3) 8 (3)

Parasitic diseases

Toxoplasmosis 6 6 (1) 0 (0) 0 (0) 0 (0) 6 (2) 6 (2)

Pneumocystosis 1 1 (,1) 0 (0) 0 (0) 0 (0) 1 (,1) 1 (,1)

Cryptosporidiosis 14 10 (1) 0 (0) 0 (0) 0 (0) 14 (5) 14 (4)

Nonclassifying parasiticenteritis

59 11 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Isosporosis 11 10 (1) 0 (0) 0 (0) 0 (0) 12 (4) 12 (3)

Malaria 129 65 (7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Nonspecific diseases

Unexplained diarrheab 736 144 (16) 0 (0) 0 (0) 39 (4) 3 (1) 3 (1)

Unexplained feverc 770 184 (20) 0 (0) 0 (0) 24 (2) 4 (1) 4 (1)

Unexplained pneumonia 12 11 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Unexplained centralneurological

25 24 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Pruritic papular eruption 212 0 (0) 0 (0) 220 (32) 0 (0) 0 (0) 0 (0)

Oral leucoplakia 1 0 (0) 0 (0) 0 (0) 1 (,1) 0 (0) 0 (0)

Oral ulcerations 146 0 (0) 0 (0) 46 (7) 0 (0) 0 (0) 0 (0)


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TreatmentIn the ANRS 1220 cohort, all patients received cotrimoxazole

regardless of CD4 cell count, even patients at WHO stage 1. In

the ANRS 1203 cohort, patients at WHO stages 2, 3, or 4 re-

ceived cotrimoxazole, irrespective of CD4 cell count, and pa-

tients at WHO stage 1 received cotrimoxazole only if their CD4

cell count dropped to ,500 cells/lL. In both cohorts, some

patients initiated ART once ART became available in Abidjan,

following WHO criteria.

Statistical AnalysisIn this study, we included only patient-time receiving co-

trimoxazole and prior to starting ART. We considered the fol-

lowing CD4 cell count strata: 0–49, 50–99, 100–199, 200–349,

350–499, 500–649, and $650 cells/lL. We estimated CD4 cell

count–specific rates of mortality and each morbidity group by

dividing the number of events that occurred in a given CD4 cell

count stratum by the cumulative time spent in the same stratum,

expressed in person-years (PY). In the literature, CD4 cell count–

specific rates are frequently estimated using 6-month periods

after the date of the latest CD4 cell count [2, 20]. In such anal-

yses, events and follow-up time that occur .6 months after

a CD4 cell count are omitted. In sub–Saharan Africa, such

omissions would likely lead to underestimated death rates, be-

cause terminally ill patients are frequently transported to their

village by their family to receive care at home. Consequently,

deaths frequently occur .6 months after the last available CD4

cell count, even though they are appropriately documented in the

databases through tracing procedures [21]. Thus, to determine

the CD4 cell count at the onset of a given event and the time

spent in a given stratum, we modeled the CD4 cell count decrease

at the individual level by use of a linear mixed model adjusted for

CD4 cell count evolution by whether or not people died. We

confirmed that this approach was suitable for the data by drawing

2 curves for the distribution of individual CD4 cell counts at each

follow-up time for patients remaining in care: the distribution of

simulated individual CD4 cell counts over time (as estimated by

the model), and the distribution of the actual CD4 cell counts

measured every 6 months. As shown in Supplementary

Appendix 2, the curves fit each other well. For a given CD4 cell

count–specific morbidity or mortality rate, follow-up within the

stratum was censored at the onset of the first event, death, time of

ART initiation, or date of last contact with the clinic.

RESULTS

Patients and Follow-upEight hundred sixty patients were included in the analysis, of

whom 94% were HIV-1 positive, 5% had dual HIV-1 and

HIV-2 positivity, and 1% were HIV-2 positive. Their baseline

characteristics are shown in Table 1. These patients were

followed up while receiving cotrimoxazole and without ART

for 2788 PY (mean follow-up per patient, 35.9 months).

During this follow-up, 262 patients died (33%). The mean

number of available CD4 cell counts was 6 per patient.

Clinical EventsTable 2 shows the overall number of episodes documented for

each specific and nonspecific disease. During follow-up, 5267

episodes of morbidity were recorded. Of these, 696 were WHO

stage 2, 1034 WHO stage 3, 283 WHO stage 4, and 338 AIDS-

defining episodes. Within the episodes of WHO stages 3 or 4 or

AIDS-defining diseases, the most frequent were oral candidiasis

(n 5 676), invasive bacterial diseases (n 5 129), esophageal

candidiasis (n 5 110), tuberculosis (n 5 84), prolonged unex-

plained fever and/or diarrhea (n 5 63), and nontuberculous

mycobacteriosis (n 5 31). The 84 episodes of tuberculosis in-

cluded 55 pulmonary cases and 29 disseminated cases. The 254

Table 2 continued.

Disease

No. of

Episodes

Overall

No. (%) of

Episodes

With Hospital

Admission

No. (%) of

Episodes With

Bacteremia

Classification, No. (%) of Episodes

WHO

Stage 2

WHO

Stage 3

WHO

Stage 4 AIDS

Hospitalization, other cause 121 121 (13) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

Malignancies 11 3 (0) 0 (0) 0 (0) 0 (0) 10 (3) 10 (3)

Overall 5267 923 (100) 137 (100) 696 (100) 1034 (100) 283 (100) 338 (100)

Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; WHO, World Health Organization.a Other invasive bacterial diseases include any other visceral bacterial diseases (meningitis, endocarditis, liver abscess, etc) and nonvisceral bacterial disease with

bacteremia.b Unexplained diarrhea includes 2 groups: unexplained diarrhea for #1 month and unexplained diarrhea for .1 month. Only episodes of the latter group are

classified as WHO stages 3 or 4. Thus, of the 736 episodes of unexplained diarrhea, only 42 (39 1 3) were classified WHO stages 3 or 4, meaning they lasted .1

month. The remaining 694 episodes lasted #1 month and did not fall into any WHO stage.c Unexplained fever includes 2 groups: unexplained fever for #1 month and unexplained fever for .1 month. Only episodes of the latter group are classified as

WHO stages 3 or 4. Of the 770 episodes of unexplained fever, only 28 (24 1 4) were classified WHO stages 3 or 4, meaning they lasted .1 month. The remaining

742 episodes lasted #1 month and did not fall into any WHO stage.


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episodes of invasive bacterial diseases were 90 enteritis cases, 59

isolated bacteremia cases, 50 pneumonia cases, 45 invasive uro-

genital infections, and 10 infections in other locations. Of these

invasive bacterial disease episodes, 39% had positive blood cul-

ture, 86% were first episodes, and 14% were recurrent episodes.

Of the 5267 recorded morbidity episodes, 923 required hospital

admission. Of the hospital admissions, 39% were due to non-

specific symptoms (unexplained fever, diarrhea, or pulmonary or

neurologic symptoms), 23% to bacterial diseases, 7% to malaria,

and 6% to tuberculosis.

CD4 Cell Count–Specific Rates of DiseasesFigure 1 shows the CD4 cell count–specific rates of death;

AIDS or death; and AIDS, death, or severe non-AIDS diseases;

the 95% confidence intervals (CIs) are shown in Supplementary

Appendix 3. As expected, the rates of AIDS or death were highest

in patients with CD4 cell counts ,200 cells/lL, ranging from

30.9 events per 100 PY in the 100–199 cells/lL stratum to 99.9

events per 100 PY in the 0–49 cells/lL stratum. Although they

were lower, the rates were still substantial in patients with

CD4 cell counts $200 cells/lL, reaching 10.4 events per 100

PY in the 200–349 cells/lL stratum, 3.7 events per 100 PY in

the 350–499 cells/lL stratum, 1.7 events per 100 PY in the

500–649 cells/lL stratum, and 0.9 events per 100 PY in the

$650 cells/lL stratum.

In CD4 cell count strata of $200 cells/lL, the most frequent

WHO stages 3 or 4 or AIDS-defining diseases were invasive

bacterial diseases, oral candidiasis, and tuberculosis (Table 3;

95% CIs are given in Supplementary Appendix 3).

DISCUSSION

In this study, we describe for the first time in Africa the CD4 cell

count–specific rates of morbidity and mortality across the full

spectrum of CD4 cell counts in HIV-infected patients receiving

cotrimoxazole but no ART. We derived these estimates from 2

long-term research cohorts in which patients had free access to

transportation and care, including diagnosis and treatment,

before the ART era.

Facilities are limited in most low-resource settings. Many

patients followed under routine conditions can afford neither the

tests required to document morbidity nor the medications to treat

it. In this context, cohorts with free access to care are likely to

generate better estimates of morbidity than are routine program

databases. On the other hand, participants in cohorts with free

access to tests and medications are also less likely to die, because of

appropriate and more rapid diagnosis and treatment. As a result,

the spectrum we describe likely reflects with reasonable accuracy

the full spectrum of HIV-related morbidity in untreated HIV-

infected patients in Cote d’Ivoire, while underestimating mor-

tality from these diseases in this population (Figure 2).

These data support the following points. First, although

mortality (4.2 events per 100 PY) and rates of AIDS or death

(10.4 events per 100 PY) in patients with CD4 cell counts of

200–349 cells/lL are lower than in those with CD4 cell counts of

,200 cells/lL, the absolute rates are still high. This is consistent

with data previously reported from South Africa (death rate,

8.0 events per 100 PY; rate of AIDS or death, 14.0 events

per 100 PY) [8] and Haiti [22], suggesting that mortality in

adults at CD4 cell counts of 200–349 cells/lL is high in some

low-resource settings compared with rates reported from

Western Europe (CHIC cohort death rate, 0.58 events per 100

PY; CHIC cohort AIDS or death rate, 4.91 events per 100 PY;

Eurosida death rate, 2.7 events per 100 PY; Eurosida AIDS rate,

6.1 events per 100 PY) [2, 20]. The novelty of the data here is

what happens at CD4 cell counts above these values, with 2

important findings: that rates of death or AIDS in patients with

CD4 cell counts of 350–499 cells/lL remain substantial (death

rate, 1.6 events per 100 PY; rate of AIDS or death, 3.7 events per

100 PY) compared with rates among HIV-infected adults with

CD4 cell counts of 350–499 cells/lL reported from Western

Europe (UK Collaborative HIV Cohort [CHIC] study death

rate, 0.32 events per 100 PY; CHIC cohort AIDS or death rate,

2.49 events per 100 PY) [2, 20] and with death rates from

causes other than HIV infection or AIDS in the overall

population (ie, HIV-infected and noninfected individuals) of

sub–Saharan African adults aged 15–59 years (global and regional

burden of disease and risk factor estimates from 2001, 0.6 deaths

per 100 PY) [23]; and that there is a trend toward decreasing

rates of mortality with increasing CD4 cell counts, even above

350 cells/lL.

Second, tuberculosis and invasive bacterial diseases are clearly

the most frequent severe diseases in patients with higher CD4

cell counts. The CD4 cell count–specific rates of tuberculosis in

this study are lower than those reported from South Africa

[7, 24] but far higher than those reported from France [25] and

Great Britain [26]. For invasive bacterial diseases, it is not

possible to compare our rates to those in other settings, because

studies that reported CD4 cell count–specific rates of bacterial

morbidity focused only on AIDS-defining recurrent episodes

[25, 26]. By doing so, they did not capture the importance of

first episodes, which in our study accounted for 85% of the

overall number of episodes of invasive bacterial diseases.

A key difference in the way in which high- and low-resource

countries consider tuberculosis and bacterial diseases is that in

rich countries these diseases are increasingly classified as non-

severe events, even when they are AIDS-defining diseases [27]. In

sub–Saharan Africa, autopsy studies have shown that tubercu-

losis and bacterial diseases are the 2 most frequent causes of

death in HIV-infected adults [12–17], even though they are

easier to diagnose and treat than many other types of opportu-

nistic infections. This is due to a combination of 3 factors: poor


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access to healthcare facilities, poor access to specific diagnostic

tests, and poor access to treatment [28]. Because of the first

2 factors, WHO estimates that only 50% of active tuberculosis

cases are diagnosed in sub–Saharan Africa [29]. As a consequence

of all 3 factors, not only is the frequency of active tuberculosis

underestimated in most HIV infection care programs, but

mortality from tuberculosis is also likely to be underestimated.

This underestimation is seen in routine programs, because most

patients with undiagnosed tuberculosis die without tuberculosis

being identified as the cause of death, and in cohort studies with

clear follow-up, because diagnosed patients receive adequate

treatment (Figure 2).

Figure 1. A, CD4 cell count–specific rates of mortality. B, CD4 cell count–specific rates of mortality for CD4 cell counts.200 cells/lL (inset in panel A).Severe non-AIDS includes the following illnesses: severe bacterial diseases (ie: bacterial diseases of any location with bacteremia, and the following visceralbacterial diseases: pneumonia, isolated bacteremia, pyelonephritis, prostatitis, orchiepididymitis, salpingitis, meningitis, endocarditis); and non–AIDS-definingcancers. Abbreviation: PY, person-years.


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Table 3. CD4-Specific Rate of Morbidity. ANRS 1203 and 1220 Cohorts, Abidjan, Cote d'Ivoire

Disease

Rate According to Current CD4 Cell Count Stratum, Events/100 PY

$650

cells/lL

500–649

cells/lL

350–499

cells/lL

200–349

cells/lL

100–199

cells/lL

50–99

cells/lL

,50

cells/lL

WHO stage 4, overall 0.0 0.8 1.5 5.6 13.3 33.1 46.7

Tuberculosis, disseminated a 0 0.3 0.3 1.9 1.6 2.9 1.6

Recurrent bacterial pneumonia 0 0 0.2 0.3 1.0 0.7 0

Recurrent NTS bacteremia 0 0 0 0.3 0.8 0.0 1.6

Nontuberculous mycobacteriosis 0 0 0.2 0.5 0.5 5.8 13.3

Cryptococcosis 0 0 0 0.4 0.5 2.2 6.5

Toxoplasmosis 0 0 0 0.1 0.3 2.1 1.7

Cryptosporidiosis,microsporidiosis

0 0 0.3 0.3 0.5 3.0 2.6

Malignancy (Kaposi sarcomaor lymphoma)

0 0 0.2 0.4 0.3 1.4 2.4

Isosporosis 0 0.3 0 0.1 1.6 2.2 0

Visceral HSV or CMV infection 0 0 0 0.3 0.8 1.5 0.8

Esophageal candidiasis 0 0.3 0.5 1.4 6.1 19.5 33.3

Chronic genital HSV infection 0 0 0 0.5 0.8 2.9 1.7

Wasting syndrome 0 0 0 0.3 0.3 0 1.6


Tuberculosis, pulmonarya 0.6 0.6 0.5 2.0 4.8 7.4 2.5

Invasive bacterial diseases,overall

3.6 3.5 3.1 9.1 17.1 18.9 16.9

Bacterial enteritis 1.7 2.0 1.5 2.9 6.2 6.6 9.1

Pneumonia 0.3 0.6 0.3 2.5 3.7 1.4 1.6

Isolated bacteremia 0.3 0.6 0.2 2.3 5.0 6.5 2.4

Urogenital infectionb 1.1 0 .3 0.8 1.4 3.1 4.3 3.2

Infection with any other organinvolvementc

0.0 0.0 0.3 0.5 0.8 0.0 0.8

Unexplained diarrhea for .1 month 0 0 0.2 0.4 2.1 6.1 11.3

Unexplained fever for .1 month 0.6 0 0.3 0.9 0.5 2.2 6.1

Oral candidiasis 3.0 4.0 4.4 12.6 32.0 72.8 89.0


Herpes zoster virus infection 3.3 4.4 2.2 7.4 11.1 6.6 2.4

Angular cheilitis 1.1 1.4 1.3 3.6 8.5 15.9 11.3

Fungal nail infections 1.5 1.4 1.9 1.9 5.7 2.9 3.3

Pruritic papular eruption 2.1 1.4 2.5 6.0 13.7 22.1 35.4

Recurrent oral ulcerations 0.3 0 0.8 1.4 2.1 4.3 2.4

Recurrent otitis or sinusitis 0.3 0.8 1.2 1.9 4.8 10.3 3.2

Nonclassifying diseases

Oral ulcerations, first episode 2.4 0.8 2.6 5.0 7.1 3.6 6.5

Otitis or sinusitis, first episode 3.3 5.3 3.4 6.5 8.8 7.3 6.6

Sinusitis, first episode 0.6 3.2 1.5 2.9 4.8 3.6 2.4

Otitis, first episode 2.6 2.0 1.8 1.8 3.3 3.7 4.0

Bacterial mucocutaneousinfectionsd

3.3 4.7 5.7 7.0 11.4 13.8 10.2

Nonclassifying fungal skininfectionse

7.7 4.2 7.0 12.3 24.0 28.3 26.6

Acute genital HSV infection 2.6 2.6 3.6 5.2 9.3 5.1 10.7

Nonclassifying parasitic enteritisf 0.9 0.3 1.3 2.1 3.2 2.9 7.1

Malaria, any episode 4.8 3.5 4.0 3.8 5.8 4.3 6.5

Malaria with hospital admission 1.4 1.1 1.7 2.3 3.1 3.6 4.8


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There are several limitations to this study. First is the lack of

facilities to diagnose some diseases. As in most studies in Africa,

even in cohort studies with the primary objective of documen-

ting morbidity, rates of all diseases are underestimated, but some

of them are underestimated to a greater extent because their

diagnosis requires sophisticated diagnostic tools. Our data

showing that the rate of nonspecific diseases that lead to hospital

admissions is high, and that this rate increases with decreasing

CD4 cell counts, illustrate this fact. In this study, we wanted to

give a comprehensive overview of the entire spectrum of mor-

bidity in our cohorts, so we recorded and reported all specific

and nonspecific episodes in order to provide a clear idea of what

diagnoses could have been missed. All nonspecific diseases are

not equivalent in terms of their likelihood of being missed. Di-

arrhea lasting #1 month and fever lasting #1 month are very

unlikely to be undiagnosed AIDS-defining diseases, because they

resolve spontaneously either without specific treatment or with

empiric antibacterial or antimalarial treatment. Thus, some ep-

isodes of these groups may be undiagnosed bacterial diseases,

undiagnosed malaria, or undiagnosed non-AIDS parasitic or

viral diarrhea, rather than undiagnosed AIDS-defining diseases.

In contrast, diarrhea lasting .1 month, fever lasting .1 month,

unexplained pneumonia, and unexplained central nervous sys-

tem symptoms could cover a wide range of undiagnosed AIDS

diseases, including severe viral diseases. However, these groups

are far smaller than the groups with diarrhea lasting #1 month

and fever lasting #1 month, and these events are almost all

restricted to CD4 cell count strata of ,350 cells/lL.

Another limitation is censoring due to loss to follow-up and

ART initiation, both of which could have been informative. The

consequence of such informative censoring is likely to be an

underestimation of deaths rather than an overestimation,

Figure 2. Differences between estimates of severe curable morbidity(severe bacterial diseases and tuberculosis) and mortality from thesediseases under research conditions and under treatment programconditions. Abbreviation: LTFU, lost to follow-up.

Table 3 continued.

Disease

Rate According to Current CD4 Cell Count Stratum, Events/100 PY

$650

cells/lL

500–649

cells/lL

350–499

cells/lL

200–349

cells/lL

100–199

cells/lL

50–99

cells/lL

,50

cells/lL

Nonspecific illness with hospitaladmission

Unexplained fever for #1 month 2.4 4.2 4.2 6.3 8.2 10.4 12.1

Unexplained diarrhea for #1 month 2.1 2.0 0.7 3.3 6.2 15.1 18.3

Unexplained central neurologicalsymptomsg

0 0.3 0.2 0.4 1.3 2.8 8.1

Unexplained pneumoniag 0 0.3 0.2 0.3 1.0 0 3.2

Any other disease with hospitaladmissionh

3.4 2.3 2.0 4.2 6.2 9.5 11.4

Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; NTS, nontyphoidal salmonella; PY, person-years; WHO, World Health Organization.a The overall rates of tuberculosis (any location) were as follows: CD4 cell count $650 cells/lL, 0.6 events per 100 PY; 500–649 cells/lL, 0.8 events per 100 PY;

350–499 cells/lL, 0.8 evens per 100 PY; 200–349 cells/lL, 4.0 events per 100 PY; 100–199 cells/lL, 6.5 events per 100 PY; 50–99 cells/lL, 10.6 events per 100 PY;

,50 cells/lL, 4.1 events per 100 PY.b Includes bacterial pyelonephritis, prostatitis orchiepididymitis, and salpingitis.c Includes any other visceral bacterial diseases (eg, meningitis or endocarditis) and nonvisceral bacterial disease (eg, sinusitis, otitis, or mucocutaneous abscess)

with bacteremia.d Includes mucocutaneous abscess and furunculosis.e Includes intertrigo, dermatophytoses, pityriasis versicolor, and tinea capita.f Includes anguillulosis, giardiasis, ankylostomiasis, intestinal bilharziosis, ascariasis, and amebiasis.g See Supplementary Appendix 1 for definitions.h Hospital admission due to any diseases not listed elsewhere in this table.


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because death rates are more likely to be higher in patients lost to

follow-up, and because patients who start ART at CD4 cell

counts of .200 cells/lL are likely to have more advanced clinical

stages of disease than patients with .200 cells/lL who remain

off ART. Had these patients not started treatment, they would

have had higher risks of death. This, together with the discussion

above regarding lower mortality from curable disease in cohort

studies compared with treatment programs, lead us to believe

that our results should be considered as lower bound estimates.

The third limitation is that we merged databases from 2 different

studies. Although both studies used the same follow-up proce-

dures and the same standardized definitions, we cannot rule out

some heterogeneity in the results. Finally, another limitation is

the sample size, which is smaller than collaborative cohorts in

industrialized countries. The mortality we found in our study has

wide confidence intervals compared with those in such cohorts.

Future collaborations of cohorts of untreated patients in low-

resource settings should be developed to refine such estimates.

In conclusion, we draw 2 key messages from these findings.

First, the very concept of HIV non-AIDS–defining diseases,

which is crucial to the current debate over when to start ART,

does not cover the same spectrum in sub–Saharan Africa as in

Western Europe, North America, and Australia. Our study

shows that rates of tuberculosis and non-AIDS infectious

diseases are substantial in patients with high CD4 cell counts.

Previous studies have consistently shown that tuberculosis and

bacterial diseases were the most important cause of death in

HIV-infected adults in sub–Saharan Africa [12–16]. Deaths

related to tuberculosis or bacterial diseases could be avoided by 2

means: improving diagnosis and treatment, and decreasing

incidence. Starting ART earlier than currently recommended

could help achieve the latter. Thus, the ongoing and future trials

of early ART in sub–Saharan Africa should carefully document

these diseases and consider them as major outcomes.

Second, because of this spectrum of illnesses, and because of

the difference in access to care, trials exploring the benefits and

risks of initiating ART at very high CD4 cell counts make more

sense in low-resource settings similar to Cote d’Ivoire than in rich

countries. Within the context of low-resource settings, starting

ART very early might make even more sense in rural settings,

which have limited facilities to diagnose tuberculosis and invasive

bacterial diseases than in urban settings, where these diseases can

be diagnosed and treated more easily.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online

(http://www.oxfordjournals.org/our_journals/cid/). Supplementary materials

consist of data provided by the author that are published to benefit the reader.

The posted materials are not copyedited. The contents of all supplementary

data are the sole responsibility of the authors. Questions or messages regarding

errors should be addressed to the author.

Notes

Acknowledgments. We are indebted to all patients who participated in

this trial. We also gratefully acknowledge the valuable contributions of the

Centre de Diagnostic et de Recherche sur le SIDA (CeDReS), Centre de

Prise en Charge et de Formation (CePReF), Centre National de Transfusion

Sanguine (CNTS), CEPAC International, and INSERM U897 teams.

Members of the ANRS 1203 and 1220 Study Groups

Clinical care in Abidjan, Cote d’Ivoire. CNTS: Hugues Abe, Nicole

Abe, Yao Abo, Emma Amon Anini, Isidore Bohouo, Ali Coulibaly, Issouf

Coulibaly, Vafoungbe Diabate, Lambert Dohoun, Daniel Ekra, Gwenola

Gourvellec, Charlotte Huet, Jules Hyda, Mamadou Konate, Seidou Konate,

Reine Kore, Charlotte Lewden, Albert Minga, Minata Ouattara, Marie-Julie

N’Dri, Sayouba Ouedraogo, Abdelh Sidibe, and Liliane Siransy. CePReF:

Xavier Anglaret, Amani Anzian, Edwidge Cisse, Nicole Dakoury-Dogbo,

Christine Danel, Joachim Gnokoro, Marie-Cecile Kassi, Mamadou Kone,

Bertin Kouadio, Yao Kouakou, Georgette Labibi, Jean Lehou, Eugene

Messou, Therese N’Dri-Yoman, Marie-Pascale Nogbout, Catherine Seyler,

Amah-Cecile Tchehy, Siaka Toure, Moussa Traore, and Marcel Zaho.

Biology, Abidjan, Cote d’Ivoire. CeDReS, CHU de Treichville: Dominique

Bonard, Patrice Combe, Arlette Emieme, Andre Inwoley, Herve Menan,

Timothee Ouassa, Francxois Rouet, Thomas-d’Aquin Toni, Ramatou Toure,

and Vincent Yapo.

Epidemiology and biostatistics, Bordeaux, France. INSERM U897:

Delphine Gabillard and Roger Salamon.

Members of the ANRS 12222 Study Group

Steering committee. Xavier Anglaret, Robert Colebunders, Francxois Da-

bis, Joseph Drabo, Serge Eholie, Delphine Gabillard, Pierre-Marie Girard,

Karine Lacombe, Christian Laurent, Vincent Le Moing, and Charlotte Lewden.

Other representatives of participating studies. Gerard Allou, Clarisse

Amani-Bosse, Divine Avit, Aida Benalycherif, Pierre de Beaudrap, Patrick

Coffie, Eric Delaporte, Lise Denoeud, Serge Diagbouga, Didier Koumavi

Ekouevi, Jean-Francxois Etard, Sabrina Eymard-Duvernay, Isabelle Fournier-

Nicolle, Herve Hien, Issouf Konate, Sinata Koulla-Shiro, Valeriane Leroy,

Olivier Marcy, Nicolas Meda, Eitel Mpoudi-Ngole, Philippe Msellati, Boubacar

Nacro, Nicolas Nagot, Ibra Ndoye, Abdoulaye Ouedraogo, Men Pagnaroat,

Roger Salamon, Vonthanak Saphonn, Olivier Segeral, Philippe Van de Perre,

and Marcel Zannou.

Financial support. This work was supported by the French Agence

Nationale de Recherche sur le SIDA et les hepatites virales, Paris, France

(grants ANRS 1203, ANRS 1220, and ANRS 12222) and the US National

Institute of Allergy and Infectious Diseases (grant NIAID AI058736).

Potential conflicts of interest. All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential

Conflicts of Interest. Conflicts that the editors consider relevant to the

content of the manuscript have been disclosed.

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